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Genome-Wide Analysis More Than Doubles Loci Linked to Osteoarthritis Risk

NEW YORK (GenomeWeb) – Researchers have identified more than 50 novel loci associated with osteoarthritis, more than doubling the number of loci linked to the condition.

About 40 percent of people over the age of 70 are affected by osteoarthritis, and scientists have previously linked nearly three dozen loci to osteoarthritis risk as well as uncovered a correlation between BMI and knee osteoarthritis risk.

Using UK Biobank and Arthritis Research UK Osteoarthritis Genetics data, researchers led by the Wellcome Sanger Institute's Eleftheria Zeggini conducted a genome-wide meta-analysis that uncovered 64 known and novel loci associated with osteoarthritis. As they reported in Nature Genetics today, the researchers noted that many of the loci they linked to the condition involved genes known to have roles in bone development disorders or collagen formation. A number are also the targets of approved therapeutics or of ones under testing.

"We have conducted the largest study of osteoarthritis to date and found over 50 new genetic changes that increase the risk of developing osteoarthritis," Zeggini, who is now at Helmholtz Zentrum München, said in a statement. "This is a major step forward in developing treatments to help the millions of people suffering from the disease."

In their GWAS meta-analysis of 77,052 cases and 378,169 controls, the researchers examined four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. Within this cohort, they identified 65 genome-wide significant variants at 64 loci, 52 of which were novel.

Nearly half of those novel signals were for osteoarthritis at any site, while 15 were specific for hip osteoarthritis, seven for knee osteoarthritis, and six for knee or hip osteoarthritis.

By folding in transcriptomic and proteomic data from tissue from patients undergoing joint replacements, the researchers found that 49 of the 64 loci they uncovered co-localized in at least one affected tissue. Meanwhile, pathway analysis found 64 biological processes linked to osteoarthritis, most of which were related to bone, cartilage, and chondrocyte morphology.

At the same time, genome-wide linkage disequilibrium-score regression analysis found links between osteoarthritis and obesity, cognition, and smoking, among other categories. Last year, Zeggini and her colleagues reported in a separate Nature Genetics paper that there was a strong genetic correlation between knee osteoarthritis and BMI. In this new study, a Mendelian randomization analysis also suggested a role for BMI and adiposity in osteoarthritis risk.

Using conditional analyses and fine-mapping, the researchers homed in on potential causal variants. For six of the novel loci, they uncovered single variants that were likely to be causal, including missense variants in SLC39A8, IL11, and ANAPC4, as well as variants near TGFB1, MAPT, and SCUBE1.

These genes were enriched for ones known to cause monogenic bone development diseases and early-onset osteoarthritis, the researchers noted.

Ten of the genes the researchers implicated have an associated therapeutic that is approved or that is in clinical trials. For instance, Invossa, a registered osteoarthritis treatment from Kolon TissueGene that's in clinical trials, targets TGFB1, which is involved in skeletal development and adult bone homeostasis, while LCL-161, which is under development to treat breast cancer, leukemia, and myeloma, targets DIABLO, which the researchers here implicated in hip osteoarthritis.

The drugs that aren't already tied to osteoarthritis could be studied for possible repositioning, according to the researchers.